Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3 + 2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives

Article abstract of DOI:10.1016/j.ejmech.2009.03.035

The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives as dipolarophiles. The structure and stereochemistry of the cycloadduct have been established by single crystal X-ray structure and spectroscopic techniques. Molecular docking studies were performed on 1FM9 protein. The synthesized compounds were screened for their antidiabetic activity on male Wistar rats.

Full text of DOI:10.1016/j.ejmech.2009.03.035

European Journal of Medicinal Chemistry 44 (2009) 3272–3279
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines
through [3 þ 2] cycloaddition reactions with thiazolidinedione
and rhodanine derivatives
,
Ramalingam Murugan a, S. Anbazhagan b, S. Sriman Narayanan c
*
a Department of Medicinal Chemistry, Orchid Research Laboratories Limited, Sholinganallur, Chennai 600119, India
b Department of Pharmaceutical Analysis, C.L. Baid Metha College of Pharmacy, Chennai 600 097, India
c Department of Analytical Chemistry, School of Chemical Science, University of Madras, Guindy Campus, Chennai 600 025, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a series of novel dispiropyrrolidines has been accomplished by 1,3-dipolar cycloaddition
reaction with 5-arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one
derivatives as dipolarophiles. The structure and stereochemistry of the cycloadduct have been estab-
lished by single crystal X-ray structure and spectroscopic techniques. Molecular docking studies were
performed on 1FM9 protein. The synthesized compounds were screened for their antidiabetic activity on
male Wistar rats.
Received 21 September 2008
Received in revised form
3 March 2009
Accepted 26 March 2009
Available online 5 April 2009
Ó 2009 Published by Elsevier Masson SAS.
Keywords:
1,3-Dipolar cycloaddition
Antidiabetic
Thiazolidinedione
Rhodanine
1. Introduction
(e.g., glipizide, glyburide), which enhance insulin resistance, and
metformin, which reduces hepatic glucose output, TZDs (e.g., tro-
Type 2 diabetes mellitus (T2DM) is a long-term disease, char-
acterized by a state of fasting hyperglycemia [1]. Type 2 or adult-
onset diabetes is a chronic metabolic disorder defined by high
levels of glucose in blood due to non-secretion of insulin. According
to recent estimates, the world diabetic population could rise to
300 million by the year 2025 due to contemporary lifestyle and
obesity [2,3]. The hyperglycemia that characterizes T2DM and that
promotes the development of complications is a consequence of at
least three metabolic abnormalities: resistance of skeletal muscle,
adipose tissue and liver to the action of insulin, inadequate insulin
secretion such that glucose is taken up from the bloodstream into
the tissues efficiently, and excessive hepatic glucose output [4].
Chronic hyperglycemia leads to a number of disorders including
cardiovascular, renal, and neurological as well as ophthalmic
infections [5–7].
glitazone, rosiglitazone, pioglitazone) improve insulin sensitivity in
liver, muscle and fat tissues and thus counteract insulin resistance
[8] (Fig. 1). Frances C. Brown reported the structural relationship
among the various 4-thiazolidinones [9]. TZDs are effective in
reducing glycosylated hemoglobin (HbA1c). It is generally recom-
mended that thiazolidinediones should be used in combination
with metformin only in obese patients [10].
Like TZDs, rhodanine based molecules have been popular as
small molecule inhibitors of numerous targets such as HCV NS3
protease [11], antidiabetic agents [12], aldose reductase [13],
b
-lactamase [14], histidine decarboxylase [15] and inhibitors of JSP-
1 [16].
The peroxisome proliferator activated receptors (PPARs) are
a group of nuclear receptor isoforms that play a key role in the
regulation of dietary fat storage and are a target for the develop-
ment of treatments for Type 2 diabetes, obesity and cardiovascular
disease. TZDs at these receptors act as insulin sensitizers, and
The treatment of Type 2 diabetes has been revolutionized with
the advent of thiazolidinediones (TZDs) class of molecules that
normalize elevated blood glucose level. Unlike sulfonylureas
PPAR
ligand specificities, PPAR
dyslipidemia in type 2 diabetic patients by down regulating cyto-
kines in adipose tissue, while agonists of the PPAR subtype
improve the atherogenic lipoprotein profile of insulin resistance
a
and PPAR
g
receptor subtypes show different tissue and
g
agonists improve glycemic control and
a
* Corresponding author. Tel.: þ91 44 22351269x226; fax: þ91 44 22352494.
E-mail address: sriman55@yahoo.com (S. Sriman Narayanan).
0223-5234/$ – see front matter Ó 2009 Published by Elsevier Masson SAS.
doi:10.1016/j.ejmech.2009.03.035

R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
3273
54–65% (Scheme 2, Table 1). There is no trace of other regioisomers
7a–p [39].
O
O
IR, 1H NMR, 13C NMR and mass spectral studies confirmed the
dispiroheterocyclic ring structures of products 6a–p. The IR spec-
trum of 6l revealed the presence of a thiocarbonyl stretching
vibration band at 1750 cmꢀ1, showing an increase of 40 cmꢀ1 from
the normal value of 1710 cmꢀ1 for 3,4-dihydroxybenzylidene-4-
thioxo-1,3-thiazolidine-2-one 6l indicating the loss of conjugation.
N
H
O
HN
S
S
OMe
CF3
HN
O
S
KRP-297
O
O
2,4-thiazolidinedione
HN
The 1H NMR spectrum of 6l revealed one sharp singlet at
to the N-methyl protons. The benzylic proton Ha exhibited
a doublet of doublets at
d 2.20 due
O
N
O
S
Pioglitazone
d
4.44 (J ¼ 10.5, 8.2 Hz). Hc of the N-CH2
O
HN
S
O
proton appeared as a doublet of doublets at
A doublet of doublets was also observed at
for the Hb proton. The aromatic protons appeared as a multiplet in
d
3.82 (J ¼ 11.5, 8.4 Hz).
N
d
3.45 (J ¼ 11.5, 8.4 Hz)
HN
N
S
O
Rhodanine
the region
and 10.81 for the NH proton of oxindole and rhodanine. Similarly,
the benzylic proton Ha exhibited a doublet of doublets at 4.45
d 6.80–7.80 and there were two broad singlets at d 9.22
O
d
Rosiglitazone
d
Fig. 1. Structure of known compounds contains thiazolidinedione.
(J ¼ 9.6, 8.2 Hz). Hc of the N-CH2 proton appeared as a doublet of
doublets at
doublet of doublets was also observed at
d
3.71 (J ¼ 12.3, 8.4 Hz) in the 1H NMR spectrum of 6a. A
d
3.42 (J ¼ 12.3, 8.4 Hz) for
[17–20]. Apart from rosiglitazone and pioglitazone, the recent drug
KRP-297 is a potent agonist of PPAR [21]. Consequently, there
continues to be interest in new compounds for clinical develop-
ment. This provides an opportunity to bring diverse class of dis-
piropyrrolidine ligands through 1,3-dipolar cycloaddition that
could normalize both insulin and glucose levels.
the Hb proton. The regiochemistry of the products 6l and 6a were
confirmed by its 1H NMR spectrum. If the other isomers had been
formed one would expect a singlet instead of doublet of doublets
for the benzylic proton. The regiochemistry of the product 6l was
also confirmed by its 13C NMR spectrum. The off resonance
g
decoupled 13C NMR of 6l exhibited signals at
d
72.6 ppm due to the
spiro carbon C3 of the pyrrolidine ring and at
d 81.7 ppm due to the
C2 spiro carbon of the pyrrolidine ring. In the same way, 13C NMR of
2. Chemistry
6a and 6g exhibited signals at
spiro carbon C3 of the pyrrolidine ring and at
80.2 ppm respectively due to the C2 spiro carbon of the pyrrolidine
ring. The resonance at 170.2 ppm and 202.1 ppm of the product
6l is due to the keto carbonyl and thiocarbonyl carbons of rhoda-
nine. The resonance at 172.1 ppm is due to the oxindole carbonyl
carbon. Signals at 37.5 ppm due to N-CH3 and at 54.5 ppm due to
N-CH2 carbons were also observed. The mass spectrum of 6l
showed a molecular ion peak at m/z 426.5 (Mꢀ), which further
confirmed the formation of the cycloadduct by the single crystal
X-ray structural analysis (Fig. 2). Likewise, the resonance at
d
69.2 ppm and 68.7 ppm due to the
Multicomponent 1,3-dipolar cycloaddition reactions are
considered to be one of the most useful processes for the
construction of five membered heterocyclic ring systems [22–24].
These five membered heterocycles are most important because of
their high regioselectivity and stereoselectivity. Spiro compounds
represent an important class of naturally occurring substances
characterized by highly pronounced biological properties [25–32].
Azomethine ylides generated by the decarboxylative route offer
a convenient method for the synthesis of nitrogen containing
heterocyclic compounds [33,34]. We herein report for the first time
the cycloaddition reaction of azomethine ylides with the olefinic
bond of 5-arylidene-1,3-thiazolidine-2,4-dione derivatives 3a–h
and 5-arylidene-4-thioxo-1,3-thiazolidine-2-one derivatives 3i–p.
Thiazolidinedione [35,36] was synthesized according to the
procedure from monochloroacetic acid and thiourea, rhodanine
[37] was synthesized from monochloroacetic acid and ammonium
thiocyanate (Scheme 1). The different substituted derivatives of 5-
arylidene-1,3-thiazolidine-2,4-dione and 5-arylidene-4-thioxo-1,3-
thiazolidine-2-one derivatives 3a–p were synthesized in accor-
dance with the literature procedure [38]. The azomethine ylides
generated by the reaction of sarcosine 5 with isatin 4 in boiling
methanol for 20–25 h reacted with double bond of 3a–h and 15–
20 h reacted with double bond of 3i–p to the corresponding
cycloadducts 6a–p as single regioisomers with overall yields of
d
80.1 ppm and
d
d
d
d
d
d
172.2 ppm and d 180.1 ppm of the product 6a is due to the keto
carbonyl carbons of thiazolidinedione. The mass spectrum of 6a–d
showed the molecular ion peak at m/z 378.4 (Mꢀ), 414.4 (Mꢀ), 384.5
(Mꢀ), 410.4 (Mꢀ), which further confirmed the formation of the
cycloadduct. Identical results were obtained with other derivatives
of thiazolidinedione and rhodanine 6a–p [40].
3. Results and discussion
In the in vivo antidiabetic study in male Wistar rats, the selective
six compounds showed better reduction in glucose levels than
rosiglitazone. Among the six compounds, particularly compounds
6b, 6h, 6j and 6p showed the best antidiabetic activity (Table 2).
Molecular docking studies were carried out on the synthesized
compounds to get insight about their binding preferences at the
active site of the receptor. The docking studies were performed on
S
H
N
1FM9 protein, viz. PPARg employing Cerius2 4.8.1 program
O
a
b
installed on silicon graphics Octane2 workstation equipped with
a 400 MHz MIPS RI2000 (512 MB RAM) running in Irix 6.5 oper-
HOOC
HOOC
Cl
Cl
H2N
NH2
O
S
ating system. All the PPARg inhibitors were modeled in cerius2
using standard bond length and bond angle parameters. Ligands
and the standards Pioglitazone, Rosiglitazone, Farglitazar and Riv-
oglitazone were docked in the active site of the PPARg using ligand
fit module [41]. The active sites were assigned at a radius of 5 Å
around the reference ligand. The docking scores of all molecules are
listed (Table 3). In the subsequent synthesis and biological
H
S
N
S
NH4CNS
O
Scheme 1. Synthesis of 2,4-thiazolidinedione and rhodanine: (a) conc. HCl, water,
reflux 10 h. (b) Et3N, dichloromethane, rt 12 h.

3274
R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
X
X
c
R
NH
NH
R-CHO
S
S
O
O
3a-p
1
2
H3C
CH2
O
N
O
d
O
N
H
COOH
N
N
H
H
5
4
X
R
NH
S
O
3a-p
O
O
Hb
S
O
Hc
HN
HN
X
S
NH
N
O
X
R
Ha
N
R
NH
Ha
Hb
Hc
7a-p
6a-p
Scheme 2. Synthesis of dispiropyrrolidine derivatives of thiazolidinedione and 4-thioxothiazolidine-2-one: Reagents and conditions: (c) piperidine, Toluene, reflux 3 h (d)
methanol, reflux 15–20 h.
evaluation of hit molecules; we found compounds 6b and 6h as
high affinity ligands for PPAR . Fig. 3(a) and (b) shows the inter-
action of the ligands with few of the critical residues (His 449,
Tyr473, Ser289 and His323) [42,43] in the active site of the PPAR
Fig. 4(a) shows the superimposition of active compounds with the
crystallized ligand GI262570 and Fig. 4(b) and (c) shows the con-
nolly surfaces of compounds 6h and 6b. The most active compound
arbitrate their antidiabetic activity through a mechanism other
than PPAR
g
g.
In general, thiazolidinediones have shown hemotoxicity and
hepatoxicity in both animal and clinical trials [47]. Serum GPT,
blood urea nitrogen and creatinine were elevated in alloxan-
induced diabetes [48] indicating that alloxan administration
produced hepatic and renal damage (Table 4). The data obviously
specify that the elevation of liver GPT and ALP values in alloxan-
induced diabetes was reduced when treated with synthesized
compounds.
g.
6h fitted the best in the active site of PPARg and attained the best
score of 71.18 amongst all molecules. It showed the important
additional H bonding interactions with the residue Tyr473 at the
active site of PPARg. This is due to the methoxy group, which is
present in fourth position of phenyl ring in compound 6h.
The synthesized molecules were showed moderate binding
score when compared to standard molecule, though they have
good antidiabetic activity in vivo. Some of the molecules like
netoglitazone, NC-2100 containing thiazolidinedione moiety
undergoing phase-II clinical trials and (D5 – unsaturated) thiazoli-
4. Conclusion
This communication illustrates simple and efficient synthesis of
regio- and stereocontrolled dispiropyrrolidine derivatives of thia-
zolidinedione and rhodanine which are found to exhibit attractive
anti-diabetic properties to male Wistar rats. The synthesized
compounds are more effective than rosiglitazone in ameliorating
stress condition. Albeit more discovery work is needed to assess the
mechanism of such dispiropyrrolidine derivatives of thiazolidine-
dione and rhodanine, present results substantiate some of its
dinediones were reported to have low or no activity at PPARg in
vitro than rosiglitazone, at the same time have high antidiabetic
activity in vivo [44–46]. These reports corroborate our surveillance
presented herein, which raise the possibility that some dis-
piropyrrolidines with thiazolidinediones and rhodanine derivatives

R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
3275
Table 1
Compounds (3a–p) used for 1,3-dipolar cycloaddition reaction.
S. No
Compound
R
X
Yield (%)
Time (h)
21
1
6a
O
61
F
2
3
4
6b
6c
6d
O
O
O
59
54
55
25
22
24
F
S
HO
HO
Fig. 2. ORTEP diagram of 6l (CCDC 653170).
F
5
6
7
6e
6f
O
O
O
59
62
61
23
20
21
antidiabetic properties. Further advanced drug design and phar-
macological studies on these compounds are underway.
MeO
5. Experimental protocols
Me
O
6g
5.1. Pharmacology
Male Wistar rats weighing 150–200 g were used for this study.
All animals were maintained under 12 h light and 12 h dark cycle at
25 ꢁ1 ꢂC. All animals were given standard chow (National Institute
of Nutrition, India) and water ad libitum. The experiments were
designed and conducted in accordance with the guidelines of
institutional animal’s ethics committee. The acclimatized animals
were kept fasting for 24 h with water ad libitum and alloxan
monohydrate (120 mg/kg i.p.) in normal saline was then adminis-
tered [49]. Serum glucose level was checked after 72 h. Animals
with serum glucose levels > 250 mg/dl were considered diabetic
and were used for the study [50]. The diabetic rats were divided
into four groups of six rats each. Control animals received distilled
water only (Group I), diabetic animals received alloxan injection
(Group II), diabetic animals orally fed with rosiglitazone (Rg) [as
0.25% carboxymethyl cellulose suspension] at dose of 36 mg/kg
(Group III) and the diabetic animals orally fed with synthesized
dispiropyrrolidine derivatives (6b, 6g, 6h, 6j, 6l and 6p) [as 0.25%
8
6h
O
65
20
O
9
6i
6j
S
S
62
60
16
20
F
10
F
S
11
12
6k
6l
S
S
55
56
15
16
HO
HO
Table 2
In vivo antidiabetic activity screening of dispiropyrrolidine derivatives.
Compound
Blood glucose in mg/dl
F
13
14
15
6m
6n
6o
S
S
S
59
62
61
17
16
16
0 h
1 h
3 h
6 h
Group I
Group II
Group III
6b
6g
6h
6j
6l
6p
185.0 ꢁ 10.5
322.2 ꢁ 8.7
317.0 ꢁ 7.4
164.0 ꢁ 6.3
315.2 ꢁ 7.2
155.0 ꢁ 5.8
134.5 ꢁ 3.7
140.5 ꢁ 2.7
133.5 ꢁ 4.8
137.5 ꢁ 11.3
175.5 ꢁ 10.7
140.5 ꢁ 14.5
157.0 ꢁ 4.5
310.4 ꢁ 6.5
145.5 ꢁ 4.3
123.5 ꢁ 4.4
136.5 ꢁ 5.4
123.8 ꢁ 3.7
112.8 ꢁ 6.7
158.5 ꢁ 5.5
106.5 ꢁ 5.8
151.0 ꢁ 3.8
297.4 ꢁ 4.5
131.0 ꢁ 4.8
115.3 ꢁ 2.2a
125.5 ꢁ 4.9b
115.8 ꢁ 1.8a
106.5 ꢁ 5.7a
120.5 ꢁ 3.5b
95.8 ꢁ 5.3a
MeO
310.0 ꢁ 10.5a
320.5 ꢁ 12.5a
315.0 ꢁ 10.2
230.5 ꢁ 8.6
275.5 ꢁ 14.5b
213.5 ꢁ 17.5
Me
O
The mean ꢁ S.E. of the blood glucose level was calculated for each group and the
results were analyzed by ANOVA and student t-test by comparing the results of 1, 3
and 6 h with 0 h. This test is applied to assess the statistical significance of difference
between two independently drawn sample means.
16
6p
S
65
15
O
a
p < 0.01indicates statistically more significant when compared with Group I.
p < 0.05 indicates statistically significant when compared with Group I.
b

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R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
Table 3
mass spectrometer. Elemental analysis was performed with Per-
kin–Elmer, 2400 series II CHN–O analyzer. The preparative chro-
matography was performed by Waters LC 4000 system includes
a Waters 2487 dual wavelength absorbance detector, Millennium
Compounds with their Cerius2 docking scores in 1FM9 (PPARg).
S. No
Compound
Dock score
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
35.62
68.80
35.72
47.72
38.56
42.35
34.56
71.18
28.32
57.65
29.44
58.34
49.25
45.28
30.25
56.87
130.38
95.27
105.78
96.48
software and a YMC C18 (ODS) column (250 ꢃ 20 mm, 10
m). Puri-
fication of synthesized compounds was carried out using water/
acetonitrile (60:40 v/v) as mobile phase at a flow rate of 25 ml/min.
Eluate from the column was monitored by UV detector at 254 nm.
5.2.1. General procedure for the synthesis of dispiropyrrolidine
derivatives of thiazolidinedione 6a–h
9
10
11
12
13
14
15
16
17
18
19
20
A mixture of isatin 4 (1.0 mmol), sarcosine 5 (1 mmol), and
5-arylidene-1,3-thiazolidine-2,4-dione (1 mmol) was refluxed in
methanol. Completion of the reaction was evidenced by TLC anal-
ysis. The solvent was then removed in vacuo and the crude
compound was subjected to preparative chromatography to afford
the cycloadduct, which was lyophilized and then crystallized from
ethanol. In the same manner, the following compounds were
obtained.
Farglitazar
Pioglitazone
Rivoglitazone
Rosiglitazone
5.2.1.1. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-211,
411-dione-4(-phenyl)-pyrrolidine (6a). Yield ¼ 61%;
[
a]
¼ ꢀ35.2
D
(c 1.0, CH2Cl2); mp 152 ꢂC IR (KBr) 1750, 1697, 1685 cmꢀ1; 1H NMR
carboxymethyl cellulose suspension] at dose of 36 mg/kg (Group
IV). The quantity of spiropyrrolidine derivatives equivalent to
average human intake of 200 mg/kg at a time was calculated for
a single dose of 36 mg/kg (for acute study). Fasting blood samples
were collected from the tail vein on third day of alloxan treatment
prior to the administration of the synthesized compounds and at 0,
1, 3, 6 h intervals. For biochemical study of the synthesized
compounds, the same animals were continued with the same dose
of the synthesized compounds once daily for 15 days. Serum
glucose levels in the blood collected at random were measured on
6, 9, 12, 15 and 18th day after alloxan treatment.
(d in CDCl3, 400 MHz) 12.1 (s, 1H),10.41 (s, 1H), 6.8–7.7 (m, 9H), 4.45
(dd, J ¼ 9.6, 8.2 Hz, 1Ha), 3.71 (dd, J ¼ 12.3, 8.4 Hz, 1Hc), 3.42 (dd,
J ¼ 12.3, 8.4 Hz, 1Hb), 2.11 (s, 3H); 13C NMR (
d in CDCl3, 400 MHz)
180.1, 172.2, 169.4, 153.2, 140.2, 139.7, 128.9, 128.5, 128.2, 126.1,
124.4, 121.5, 80.1, 69.2, 54.5, 36.5, 32.2 ppm; m/z 378.4 (Mꢀ).
Analysis calcd for C20H17N3O3S: C, 63.31; H, 4.52; N, 11.07; S, 8.45.
Found: C, 63.28; H, 4.62; N, 11.02; S, 8.43%.
5.2.1.2. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211, 411-dione-4-(3,4-diflurophenyl)-pyrrolidine (6b). Yield ¼ 59%;
[a
]D ¼ ꢀ44.1 (c 1.0, CH2Cl2); mp 158 ꢂC IR (KBr) 1747, 1687,
1677 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 11.8 (s, 1H), 10.32 (s, 1H),
5.2. Synthesis
6.8–7.7 (m, 7H), 4.32 (dd, J ¼ 9.7, 8.3 Hz, 1Ha), 3.65 (dd, J ¼ 12.4,
8.2 Hz, 1Hc), 3.32 (dd, J ¼ 12.4, 8.2 Hz, 1Hb), 2.08 (s, 3H); 13C NMR (
d
Melting points were determined on Veego melting point
apparatus and are uncorrected. Infra red spectra were recorded on
Perkin–Elmer FT-IR 1600 spectrometer. Proton (1H NMR) and
carbon (13C NMR) nuclear magnetic resonance spectra were
recorded on Bruker Avance 400 MHz spectrometer with TMS as the
internal standard. Mass spectra were recorded on Agilent MSD VL
in CDCl3, 400 MHz) 179.6, 172.0, 167.3, 153.1, 149.4, 147.1, 140.2,
135.9, 128.4, 126.2, 125.1, 122.4, 121.3, 118.1, 80.2, 69.1, 53.5, 37.4,
33.4 ppm; m/z 414.4 (Mꢀ). Analysis calcd for C20H15F2N3O3S: C,
57.83; H, 3.64; N, 10.12; S, 7.72. Found: C, 57.78; H, 3.61; N, 10.10; S,
7.82%.
Fig. 3. (a) Compound 6h with PPAR
g (1FM9). (b) Compound 6b with PPARg (1FM9). It shows the binding mode of ligands in the active site. The side chains of the residues are
shown in stick model. Yellow color ribbon represents the secondary structure of the protein.

R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
3277
Fig. 4. (a) The superimposition of active compounds 6h and 6b with GI262570 (crystallized ligand). (b) Connolly surface of compounds 6h and 6b.
5.2.1.3. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211, 411-dione-4-(thiophene-2-yl)-pyrrolidine (6c). Yield ¼ 54%;
384.5 (Mꢀ). Analysis calcd for C18H15N3O3S2: C, 56.09; H, 3.92; N,
10.90; S, 10.64. Found: C, 56.11; H, 3.87; N, 10.79; S, 16.78%.
[
a]
¼ ꢀ37.4 (c 1.0, CH2Cl2); mp 153 ꢂC IR (KBr) 1755, 1688,
D
1679 cmꢀ1; 1H NMR (
d
in CDCl3, 400 MHz) 11.2 (s, 1H), 9.61 (s, 1H),
5.2.1.4. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-211,
6.9–7.5 (m, 7H), 4.12 (dd, J ¼ 8.9, 7.8 Hz, 1Ha), 3.45 (dd, J ¼ 11.8,
411-dione-4-(3,4-dihydroxyphenyl)-pyrrolidine
(6d). Yield ¼ 55%;
8.2 Hz, 1Hc), 3.32 (dd, J ¼ 11.8, 8.2 Hz, 1Hb), 2.20 (s, 3H); 13C NMR (
d
[a
]D ¼ ꢀ37.6 (c 1.0, CH2Cl2); mp 155 ꢂC IR (KBr) 1765, 1689,
in CDCl3, 400 MHz) 179.7, 172.2, 167.2, 152.3, 144.8, 140.1, 128.2,
1665 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 10.53 (s,1H), 8.95 (s,1H),
126.3, 126.2, 124.1, 123.2, 121.4, 79.8, 69.6, 54.4, 37.5, 32.4 ppm; m/z
6.8–7.8 (m, 7H), 4.25 (dd, J ¼ 9.6, 8.2 Hz, 1Ha), 3.41 (dd, J ¼ 12.3,
8.4 Hz, 1Hc), 3.22 (dd, J ¼ 12.3, 8.4 Hz, 1Hb), 2.11 (s, 3H); 13C NMR (
d
in CDCl3, 400 MHz) 179.5, 172.8, 167.4, 152.4, 147.6, 144.4, 139.8,
132.8, 128.4, 126.6, 124.3, 122.7, 121.2, 117.3, 79.5, 68.7, 53.6, 37.5,
33.2 ppm; m/z 410.4 (Mꢀ). Analysis calcd for C20H17N3O5S: C, 58.38;
H, 4.16; N, 10.21; S, 7.79. Found: C, 58.34; H, 4.24; N, 10.22; S, 7.74%.
Table 4
Biochemical parameters in alloxan-induced diabetic rats at 18th day.
Seruma
Blooda
Livera
Treatment
(dose/kg b.wt)
GPT (U/ml)
Creatinine Urea
GPT
ALP
(mg/dl)
nitrogen
(mg/dl)
(U/mg
protein)
(KA/dl)
5.2.1.5. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211,
411-dione-4-(4-flurophenyl)-pyrrolidine
(6e). Yield ¼ 59%;
82.5 ꢁ 15.5
0.8 ꢁ 0.25
17.5 ꢁ 2.0 525.1 ꢁ 55.3
34.0 ꢁ 3.5 Group I
55.5 ꢁ 6.5 Group II
55.5 ꢁ 6.5 Group III
41.3 ꢁ 5.5 6b
[a
]
¼ ꢀ45.3 (c 1.0, CH2Cl2); mp 150 ꢂC IR (KBr) 1755, 1692,
D
312.5 ꢁ 15.5 3.0 ꢁ 0.50 62.0 ꢁ 3.5 870.5 ꢁ 59.0
150.2 ꢁ 15.5 2.2 ꢁ 0.10
132.0 ꢁ 26.2b 2.1 ꢁ 0.15
129.8 ꢁ 28.3b 1.8 ꢁ 0.15
140.5 ꢁ 15.8 1.8 ꢁ 0.15
137.5 ꢁ 19.5b 1.5 ꢁ 0.10
142.8 ꢁ 17.2 2.0 ꢁ 0.10
121.0 ꢁ 12.2b 2.2 ꢁ 0.15
55.0 ꢁ 2.5 725.0 ꢁ 32.0
35.0 ꢁ 2.5b 582.5 ꢁ 48.5
37.5 ꢁ 1.8b 557.5 ꢁ 46.5
41.8 ꢁ 3.2 698.0 ꢁ 54.6
38.5 ꢁ 1.5b 625.6 ꢁ 69.6
39.0 ꢁ 3.8 645.5 ꢁ 42.5
35.5 ꢁ 2.5b 575.6 ꢁ 35.5
1668 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 11.51 (s, 1H), 9.31 (s, 1H),
6.8–7.7 (m, 8H), 4.25 (dd, J ¼ 9.4, 8.2 Hz, 1Ha), 3.42 (dd, J ¼ 11.8,
38.3 ꢁ 3.8 6g
8.2 Hz, 1Hc), 3.24 (dd, J ¼ 11.8, 8.2 Hz, 1Hb), 2.08 (s, 3H); 13C NMR (
d
48.5 ꢁ 4.5 6h
in CDCl3, 400 MHz) 180.1, 172.5, 167.4, 160.3, 152.3, 139.5, 134.7,
129.8, 128.4, 126.2, 124.2, 121.4, 115.6, 79.7, 68.9, 53.6, 37.4,
33.2 ppm; m/z 396.4 (Mꢀ). Analysis calcd for C20H16FN3O3S: C,
60.44; H, 4.06; N, 10.57; S, 8.07: Found: C, 60.38; H, 4.13; N, 10.48; S,
8.15%.
37.0 ꢁ 5.5 6j
43.8 ꢁ 5.5 6l
42.3 ꢁ 4.0 6p
a
All values are mean ꢁ SD, n ¼ 6.
b
p < 0.001 when compared with Group I.

3278
R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
5.2.1.6. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211, 411-dione-4-(4-methoxyphenyl)-pyrrolidine (6f). Yield ¼ 62%;
126.2, 125.2, 124.2, 121.4, 117.8, 115.6, 85.6, 82.4, 55.6, 39.2,
37.9 ppm; m/z 430.5 (Mꢀ). Analysis calcd for C20H15F2N3O2S2: C,
55.67; H, 3.50; N, 9.74; S, 14.86. Found: C, 55.64; H, 3.54; N, 9.68; S,
14.91%.
[
a]
¼ ꢀ42.3 (c 1.0, CH2Cl2); mp 154 ꢂC IR (KBr) 1762, 1689,
D
1665 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 11.2 (s, 1H), 9.87 (s, 1H),
6.8–7.7 (m, 8H), 4.32 (dd, J ¼ 9.4, 8.3 Hz, 1Ha), 3.42 (dd, J ¼ 12.3,
5.2.2.3. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thia-
zolidine-211-one-4-(thiophene-2-yl)-pyrrolidine (6k). Yield ¼ 55%;
8.4 Hz, 1Hc), 3.35 (dd, J ¼ 12.3, 8.4 Hz, 1Hb), 3.75 (s, 3H) 2.12 (s, 3H);
13C NMR (
d in CDCl3, 400 MHz) 180.2, 173.4, 168.3, 158.0, 152.2,
[a
]D ¼ ꢀ35.2 (c 1.0, CH2Cl2); mp 141 ꢂC IR (KBr) 1758, 1645 cmꢀ1; 1H
139.7, 131.8, 129.4, 128.5, 126.2, 124.2, 121.4, 114.5, 80.2, 69.4, 58.5,
54.5, 38.1, 33.7 ppm; m/z 408.4 (Mꢀ). Analysis calcd for
C20H19N3O4S: C, 61.60; H, 4.68; N, 10.26; S, 7.83. Found: C, 61.57; H,
4.68; N, 10.33; S, 7.79%.
NMR (d in CDCl3, 400 MHz) 9.90 (s, 1H), 8.85 (s, 1H), 6.8–7.8 (m, 7H),
4.42 (dd, J ¼ 10.5, 8.2 Hz, 1Ha), 3.85 (dd, J ¼ 11.5, 8.4 Hz, 1Hc), 3.42
(dd, J ¼ 11.8, 8.4 Hz, 1Hb), 2.18 (s, 3H); 13C NMR (
d in CDCl3,
400 MHz) 203.8, 174.5, 170.9, 155.4, 145.5, 140.7, 128.4, 126.3, 126.2,
123.2, 122.4, 121.4, 85.6, 82.7, 55.6, 38.9, 38.2 ppm; m/z 400.5 (Mꢀ).
Analysis calcd for C18H15N3O2S3: C, 53.84; H, 3.77; N, 10.47; S, 23.96.
Found: C, 53.79; H, 3.85; N, 10.37; S, 24.03%.
5.2.1.7. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211, 411-dione-4-(4-methylphenyl)-pyrrolidine (6g). Yield ¼ 61%;
[
a]
¼ ꢀ41.3 (c 1.0, CH2Cl2); mp 157 ꢂC IR (KBr) 1755, 1693,
D
1658 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 11.8 (s, 1H), 10.34 (s, 1H),
6.8–7.7 (m, 8H), 4.32 (dd, J ¼ 9.6, 8.2 Hz, 1Ha), 3.52 (dd, J ¼ 12.3,
5.2.2.4. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thia-
zolidine-211-one-4-(3,4-dihydroxyphenyl)-pyrrolidine (6l). Yield ¼ 56%;
8.4 Hz, 1Hc), 3.25 (dd, J ¼ 12.3, 8.4 Hz, 1Hb), 2.62 (s, 3H) 2.11 (s, 3H);
13C NMR (
d in CDCl3, 400 MHz) 179.2, 172.9, 168.5, 152.6, 140.2,
[a
]D ¼ ꢀ36.1 (c 1.0, CH2Cl2); mp 138 ꢂC IR (KBr) 1725, 1654 cmꢀ1; 1H
135.8, 134.9, 129.2, 128.4, 128.1, 126.2, 124.2, 121.4, 80.2, 68.7, 54.3,
37.5, 33.8 ppm; m/z 392.5 (Mꢀ). Analysis calcd for C21H19N3O3S: C,
64.10; H, 4.87; N, 10.68; S, 8.15. Found: C, 64.21; H, 4.77; N, 10.72; S,
8.10%.
NMR (d in CDCl3, 400 MHz) 10.81 (s, 1H), 9.22 (s, 1H), 6.8–7.8 (m, 7H),
4.88 (s, 2H), 4.44 (dd, J ¼ 10.5, 8.2 Hz, 1Ha), 3.82 (dd, J ¼ 11.5, 8.4 Hz,
1Hc), 3.45 (dd, J ¼ 11.8, 8.4 Hz, 1Hb), 2.20 (s, 3H); 13C NMR (
d in CDCl3,
400 MHz) 202.1, 172.1, 170.2, 154.5, 147.6, 145.7, 139.2, 128.6, 126.5,
124.6, 122.3, 121.4, 117.8, 115.5, 81.7, 72.6, 54.5, 38.1, 37.5 ppm; m/z
426.5 (Mꢀ). Analysis calcd for C20H17N3O4S2: C, 56.19; H, 4.01; N, 9.83;
S, 15.00. Found: C, 56.10; H, 3.98; N, 9.88; S, 15.07%.
5.2.1.8. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] thiazolidine-
211, 411-dione-4-(3,4-dimethoxyphenyl)-pyrrolidine (6h). Yield 65%;
[
a]
¼ ꢀ46.2 (c 1.0, CH2Cl2); mp ¼ 150 ꢂC; IR (KBr) 1752, 1697,
D
1666 cmꢀ1; 1H NMR (
d in CDCl3, 400 MHz) 11.10 (s, 1H), 9.82 (s, 1H),
5.2.2.5. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-
thiazolidine-211-one-4-(4-flurophenyl)-pyrrolidine (6m). Yield ¼ 59%;
6.8–7.7 (m, 7H), 4.42 (dd, J ¼ 9.4, 8.2 Hz, 1Ha), 3.71 (dd, J ¼ 12.3,
8.4 Hz, 1Hc), 3.42 (dd, J ¼ 12.3, 8.4 Hz, 1Hb), 3.75 (s, 6H) 2.11 (s, 3H);
[
a
]D ¼ ꢀ43.8 (c 1.0, CH2Cl2); mp 139 ꢂC IR (KBr) 1748, 1658 cmꢀ1; 1H
13C NMR (
d in CDCl3, 400 MHz) 180.2, 173.2, 168.4, 153.1, 150.2,
NMR (d in CDCl3, 400 MHz) 11.2 (s, 1H), 10.32 (s, 1H), 6.8–7.8 (m, 8H),
147.4, 140.2, 132.8, 128.6, 126.4, 124.2, 121.8, 116.4, 113.5, 70.2, 69.3,
56.8, 56.7, 55.3, 38.4, 32.5 ppm; m/z 422.5 (Mꢀ). Analysis calcd for
C22H21N3O4S: C, 62.40; H, 5.00; N, 9.92; S, 7.57. Found: C, 62.38; H,
5.12; N, 9.87; S, 7.52%.
4.41 (dd, J ¼ 9.5, 7.9 Hz, 1Ha), 3.82 (dd, J ¼ 11.8, 8.5 Hz, 1Hc), 3.44 (dd,
J ¼ 11.8, 8.5 Hz, 1Hb), 2.18 (s, 3H); 13C NMR (
d in CDCl3, 400 MHz)
204.3,173.2,170.4,161.4,153.7,139.8,134.5,129.8,129.2,126.4,122.2,
121.4, 115.4, 85.7, 82.6, 54.5, 39.7, 38.2 ppm; m/z 412.5 (Mꢀ). Analysis
calcd for C20H16FN3O2S2: C, 58.09; H, 3.90; N, 10.16; S, 15.51. Found:
C, 58.11; H, 4.03; N, 10.08; S, 15.44%.
5.2.2. General procedure for the synthesis of dispiropyrrolidine
derivatives of rhodanine 6i–p
A mixture of isatin 4 (1.0 mmol), sarcosine 5 (1 mmol), and
5.2.2.6. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thia-
zolidine-211-one-4-(4-methoxyphenyl)-pyrrolidine (6n). Yield ¼ 62%;
5-arylidene-4-thioxo-1,3-thiazolidine-2-one
(1 mmol)
was
refluxed in methanol. Completion of the reaction was evidenced by
TLC analysis. The solvent was then removed in vacuo and the crude
compound was subjected to preparative chromatography to afford
the cycloadduct, which was lyophilized and then crystallized from
ethanol. In the same manner, the following compounds were
obtained.
[a
]D ¼ ꢀ41.4 (c 1.0, CH2Cl2); mp 138 ꢂC IR (KBr) 1767, 1644 cmꢀ1; 1H
NMR (d in CDCl3, 400 MHz) 11.50 (s,1H), 9.85 (s,1H), 6.8–7.8 (m, 8H),
4.42 (dd, J ¼ 9.5, 7.9 Hz, 1Ha), 3.75 (dd, J ¼ 11.4, 8.5 Hz, 1Hc), 3.39 (dd,
J ¼ 11.4, 8.5 Hz, 1Hb), 3.82 (s, 3H); 2.15 (s, 3H); 13C NMR (
d in CDCl3,
400 MHz) 202.6, 172.8, 170.4, 159.2, 153.4, 140.7, 132.6, 129.2, 128.4,
126.2, 124.3, 121.6, 114.4, 84.7, 82.4, 56.0, 54.1, 38.6, 37.4 ppm; m/z
424.5 (Mꢀ). Analysis calcd for C21H19N3O3S2: C, 59.27; H, 4.50; N,
9.87; S, 15.07. Found: C, 59.31; H, 4.49; N, 9.81; S, 15.10%.
5.2.2.1. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-
thiazolidine-211-one-4-(phenyl)-pyrrolidine
(6i). Yield ¼ 62%;
[
a]
¼ ꢀ33.1 (c 1.0, CH2Cl2); mp 156 ꢂC IR (KBr) 1714, 1645 cmꢀ1; 1H
D
NMR (
d
in CDCl3, 400 MHz) 11.0 (s, 1H), 8.82 (s, 1H), 6.8–7.8 (m, 9H),
5.2.2.7. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thia-
zolidine-211-one-4-(4-methyl phenyl)-pyrrolidine (6o). Yield ¼ 61%;
4.48 (dd, J ¼ 10.1, 8.5 Hz, 1Ha), 3.85 (dd, J ¼ 11.8, 8.4 Hz, 1Hc), 3.44
(dd, J ¼ 11.8, 8.4 Hz, 1Hb), 2.21 (s, 3H); 13C NMR (
d
in CDCl3,
[
a
]D ¼ ꢀ39.7 (c 1.0, CH2Cl2); mp 142 ꢂC IR (KBr) 1754, 1632 cmꢀ1; 1H
400 MHz) 202.4, 172.5, 170.6, 153.1, 140.4, 138.9, 128.9, 128.4, 128.2,
126.2, 126.1, 124.2, 121.4, 85.2, 81.4, 55.3, 39.4, 37.6 ppm; m/z 394.5
(Mꢀ). Analysis calcd for C20H17N3O2S2: C, 60.74; H, 4.33; N, 10.62; S,
16.22: Found: C, 60.66; H, 4.41; N, 10.52; S, 16.32%.
NMR (d in CDCl3, 400 MHz) 10.88 (s,1H), 9.86 (s,1H), 6.8–7.8 (m, 8H),
4.28 (dd, J ¼ 9.6, 8.1 Hz,1Ha), 3.45 (dd, J ¼ 11.4, 8.5 Hz, 1Hc), 3.24 (dd,
J ¼ 11.4, 8.5 Hz, 1Hb), 2.56 (s, 3H) 2.21 (s, 3H); 13C NMR (
d in CDCl3,
400 MHz) 201.3, 172.8, 170.2, 152.6, 139.7, 135.7, 135.6, 129.2, 128.4,
128.1, 126.2, 124.2, 121.4, 85.3, 82.4, 58.4, 38.6, 36.5, 25.4 ppm; m/z
408.5 (Mꢀ). Analysis calcd for C21H19N3O2S2: C, 61.59; H, 4.68; N,
10.26; S, 15.66. Found: C, 61.55; H, 4.71; N, 10.19; S, 15.74%.
5.2.2.2. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thia-
zolidine-211-one-4-(3,4-difluro phenyl)-pyrrolidine (6j). Yield ¼ 60%;
[a
]D ¼ ꢀ45.6 (c 1.0, CH2Cl2); mp 150 ꢂC IR (KBr) 1757, 1638 cmꢀ1; 1H
NMR (
d
in CDCl3, 400 MHz) 11.10 (s,1H), 9.85 (s,1H), 6.8–7.8 (m, 7H),
5.2.2.8. 1-N-methyl-spiro [2.31] oxindole-spiro [3.511] 411-thioxo-thiazo-
lidine-211-one-4-(3,4-dimethoxyphenyl)-pyrrolidine (6p). Yield ¼ 65%;
4.51 (dd, J ¼ 10.2, 8.4 Hz, 1Ha), 3.82 (dd, J ¼ 11.8, 8.4 Hz, 1Hc), 3.42
(dd, J ¼ 11.8, 8.4 Hz, 1Hb), 2.17 (s, 3H); 13C NMR (
d
in CDCl3,
[
a
]D ¼ ꢀ45.4 (c 1.0, CH2Cl2); mp 140 ꢂC IR (KBr) 1736, 1647 cmꢀ1; 1H
400 MHz) 203.8, 173.4, 170.4, 153.3, 150.2, 147.4, 140.2, 136.5, 128.4,
NMR (d in CDCl3, 400 MHz) 11.5 (s, 1H), 10.20 (s, 1H), 6.8–7.8 (m, 7H),

R. Murugan et al. / European Journal of Medicinal Chemistry 44 (2009) 3272–3279
3279
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R. Sapestein, R.G. Smith, M.D. Leibowitz, Endocrinology 137 (1996) 4189–4195.
[21] M. Nomura, S. Kinoshita, H. Satoh, T. Maeda, K. Murakami, M. Tsunoda,
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[22] O. Tsuge, S. Kanemasa, A.R. Katritzky (Eds.), Advances in Heterocyclic Chem-
istry, Academic, San Diego, CA, 1989.
4.44 (dd, J ¼ 9.5, 7.9 Hz, 1Ha), 3.82 (dd, J ¼ 11.4, 8.5 Hz, Hc), 3.42 (dd,
J ¼ 11.4, 8.5 Hz, 1Hb), 3.88 (s, 6H) 2.21 (s, 3H); 13C NMR (
d in CDCl3,
400 MHz) 201.4, 171.6, 170.2, 153.0, 148.4, 145.6, 128.4, 126.2, 124.2,
122.2, 121.4, 84.6, 80.3, 53.4, 38.7, 36.8 ppm; m/z 454.5 (Mꢀ). Analysis
calcd for C20H17N3O4S2: C, 56.19; H, 4.01; N, 9.83; S, 15.00. Found: C,
56.11; H, 4.08; N, 9.76; S, 15.08%.
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[24] R. Grigg, V. Sridharan, D.P. Curran (Eds.), Advances in Cycloaddition, Jai, Lon-
don, 1993.
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One of the authors, R.M. wishes to thank Dr. Raghavendra Rao,
Managing Director of Orchid Research Laboratories Limited
(www.orchidpharma.com), Chennai, India, for consent to perform
the research and Professor. R. Raghunathan, Department of Organic
Chemistry, University of Madras, Chennai, India for the valuable
discussion.
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